Copper chelation therapy is most often associated with Wilson's disease, an autosomal recessive disorder of copper metabolism. In this disorder, the excretion of copper into the bile appears to be defective, and reduced hepatic incorporation of copper into ceruloplasmin occurs, leading to an accumulation of copper in plasma and body tissues. Wilson's disease often leads to hepatic and/or neurologic dysfunction, and premature osteoarthritis. Two commonly used copper chelators for the treatment of Wilson's disease are D-penicillamine (DPA) and triethylenetetramine (trientine or TRIEN).
Patients with rheumatoid arthritis show elevated levels of copper and copper-binding protein, ceruloplasmin, in serum and in synovial fluid, and copper chelation therapy has been suggested for patients with rheumatoid arthritis and other inflammatory diseases (Milanino R. et al., Copper Metabolism in the Acute Inflammatory Process and its Possible Significance for a Novel Approach to the therapy of Inflammation. Int. J. Tiss. Reac. (1985) VII(6):469-474). Complexing drugs with copper has also been suggested to improve the efficacy of anti-inflammatory medications (Sorenson J. R. J. In: Milanino R. et al. editors. Copper and zinc in inflammation. Dordrecht: Kluwer Academic Publishers (1989):69-84). However, the various effects of copper on the inflammatory response in different tissues have not yet been thoroughly elucidated (Jeremy J. Y. et al. Copper Chelators Inhibit Platelet Thromboxane A2 Synthesis and Lipoxygenase Activity, in vitro. J. Drug Dev. Clin. Pract. (1995) 7:119-126). For example, it has been suggested that copper depletion, including depletion by treatment with copper chelators, may reduce levels of ceruloplasmin and thereby exacerbate some measures of occular inflammation (McGahan M. C. et al. Effects of Copper Depletion and D-penicillamine Treatment of the Ocular Inflammatory Response. Agents and Actions (1991) 34(3):405-509). Choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) is a leading cause of severe vision loss in elderly people. Therapies for CNV have included laser photocoagulation and photodynamic therapy (PDT, such as methods disclosed in, but not limited to, U.S. Pat. No. 5,171,749 issued Dec. 15, 1992, incorporated herein by reference). The former uses a thermal laser to destroy capillaries, with nonselective tissue damage. The latter is a relatively new therapy employing a photosensitizer, which is activated by a non-thermal laser. The therapeutic effect of PDT is generally thought to result at least partially from the formation of reactive oxygen species (ROS) or free radicals, which are cytotoxic.
Laser therapy, however, can also generate an inflammatory response, which can result in damage of normal tissue and recurrence of neovascularization, compromising therapeutic efficacy. It has been suggested that an inflammatory response, secondary to laser treatment, may play a role in inducing pathological side effects (Schmidt-Erfurth U., et al., Photodynamic therapy with verteporfin for choroidal neovascularization caused by age-related macular degeneration: results of retreatments in a phase 1 and 2 study. Arch Ophthalmol, (1999) 117(9): 1177-87; Ciulla T. A., et al., Age-related macular degeneration: a review of experimental treatments. Surv Ophthalmol, (1998) 43(2):134-46; Jackson J. R., et al., The codependence of angiogenesis and chronic inflammation. Faseb J, (1997) 11(6):457-65; Majno G., Chronic inflammation: links with angiogenesis and wound healing. Am J Pathol, (1998) 153(4):1035-9).